regorafenib   Click here for help

GtoPdb Ligand ID: 5891

Synonyms: BAY 73-4506 | Stivarga®
Approved drug
regorafenib is an approved drug (FDA (2012), EMA (2013))
Compound class: Synthetic organic
Comment: Regorafenib is an inhibitor of multiple membrane-bound and intracellular kinases. Although the drug is approved it must carry a Boxed Warning alerting patients and clinicians that severe and fatal liver toxicity was observed in some patients in regorafenib clinical studies. Regorafenib is a Type-2 kinase inhibitor.
Click here for help

Ligand Activity Visualisation Charts

These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.

✖

View interactive charts of activity data across species

IUPHAR Pharmacology Education Project (PEP) logo

View more information in the IUPHAR Pharmacology Education Project: regorafenib

2D Structure
Click here for help

2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

✖
Click here for structure editor
Physico-chemical Properties
Click here for help

Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the CDK toolkit. All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

✖
Hydrogen bond acceptors 6
Hydrogen bond donors 3
Rotatable bonds 9
Topological polar surface area 92.35
Molecular weight 482.08
XLogP 3.91
No. Lipinski's rules broken 0
SMILES / InChI / InChIKey
Click here for help

SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

✖
Canonical SMILES CNC(=O)c1nccc(c1)Oc1ccc(c(c1)F)NC(=O)Nc1ccc(c(c1)C(F)(F)F)Cl
Isomeric SMILES CNC(=O)c1nccc(c1)Oc1ccc(c(c1)F)NC(=O)Nc1ccc(c(c1)C(F)(F)F)Cl
InChI InChI=1S/C21H15ClF4N4O3/c1-27-19(31)18-10-13(6-7-28-18)33-12-3-5-17(16(23)9-12)30-20(32)29-11-2-4-15(22)14(8-11)21(24,25)26/h2-10H,1H3,(H,27,31)(H2,29,30,32)
InChI Key FNHKPVJBJVTLMP-UHFFFAOYSA-N
No information available.
Summary of Clinical Use Click here for help
Regorafenib is used to treat metastatic colorectal cancer and advanced gastrointestinal stromal tumours. In April 2017 the US FDA expanded approval to include treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.
Mechanism Of Action and Pharmacodynamic Effects Click here for help
Regorafenib is an orally-administered inhibitor of multiple kinases involved in various signaling pathways involved in tumor growth, including pathological processes such as oncogenesis, tumor angiogenesis, and maintenance of the tumor microenvironment. Inhibition of VEGFR2 and TIE2 may account for the drug's anti-angiogenic properties.
Pharmacokinetics Click here for help
Absorption/Distribution
Regorafenib circulates in the enterohepatic system and is almost completely bound to plasma proteins (99.5%).
Biotransformation/Metabolism
CYP3A4 and UGT1A9 generate the metabolites of regorafenib, M-2 (N-oxide; BAY 75-7495) and M-5 (N-oxide and N-desmethyl; BAY 81-8752) which have similar in vitro pharmacological activities and steady-state concentrations as regorafenib [1].
Elimination
In vivo excretion of radiolabelled regorafinib indicates that after 12 days a total of 90% was eliminated (71% in feces and 19% in urine).
External links Click here for help
For extended ADME data see the following:

Electronic Medicines Compendium (eMC)
Drugs.com
European Medicines Agency (EMA)